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. 2023 Sep 3;37(5):2128–2133. doi: 10.21873/invivo.13309

A Preliminary Study of Pharmacokinetics and Pharmacodynamics of Oral Fingolimod in Dogs

TAESIK YUN 1, JONG-WOO JEONG 2, YOONHOI KOO 1, YEON CHAE 1, DOHEE LEE 1, HAKHYUN KIM 1, SOOCHONG KIM 3, MHAN-PYO YANG 1, KYEONG-RYOON LEE 2,4, BYEONG-TECK KANG 1
PMCID: PMC10500503  PMID: 37652477

Abstract

Background/Aim

Fingolimod is a sphingosine-1-phosphate receptor modulator that prevents lymphocytes egress from lymphoid organs. It has been used as a disease-modifying drug for human multiple sclerosis and has shown better therapeutic effects than other conventional therapies. Therefore, this study was performed to obtain preclinical data of fingolimod in dogs.

Materials and Methods

Nine laboratory Beagle dogs were used and randomized into three groups for pharmacokinetics (PK) and pharmacodynamics (PD). The dogs were administered once with a low-dose (0.01 mg/kg, n=3), medium-dose (0.05 mg/kg, n=3), and high-dose (0.1 mg/kg, n=3) of fingolimod, orally. Samples were collected serially at predetermined time points, and whole blood fingolimod concentrations were measured using high-performance liquid chromatography-mass spectrometry. Differential counts of leukocytes over time were determined to identify immune cells’ response to fingolimod.

Results

Regarding PK, the concentration of fingolimod in the blood increased in a dose-dependent manner, but it was not proportional. Regarding PD, the number of lymphocytes significantly decreased compared to baseline in all dose groups (low-dose, p=0.0002; medium-dose, p<0.0001; high-dose, p=0.0012). Eosinophils were significantly reduced in low- (p=0.0006) and medium- (p=0.0006) doses, and neutrophils were also significantly reduced in medium- (p=0.0345) and high- (p=0.0016) doses.

Conclusion

This study provides the basis for future clinical applications of fingolimod in dogs with immune-mediated diseases, such as meningoencephalitis of unknown etiology.

Keywords: FTY720, meningoencephalitis of unknown etiology, MUE, S1PR1, sphingosine-1-phosphate receptor 1, S1PR modulator

Fingolimod (FTY720) is a novel, immune-modulatory agent currently used to treat relapsing and remitting multiple sclerosis (MS), a chronic inflammatory demyelinating disease of central nervous system (CNS) (1-3). It is a sphingosine-1-phosphate receptor (S1PR) modulator that prevents egression of lymphocytes from lymph nodes and results in fewer lymphocytes of peripheral circulation (4,5). Fingolimod has shown better therapeutic effects than conventional treatment agents: it reduced the annualized relapse rate of MS by 54-60% and 38-52% compared to the placebo group and interferon beta-1a group, respectively (1,6). In veterinary medicine, except for preclinical trials before application in humans, there is only one report about fingolimod in healthy dogs to identify the pathogenesis of inflammatory bowel disease (7).

The main treatment method of meningoencephalitis of unknown etiology (MUE) is glucocorticoids combined with other immunosuppressive agents (8). However, despite aggressive immunosuppressive treatment, the median survival time of dogs with MUE is very short; 28-357 days in glucocorticoids alone and 240-590 days in combination therapy with glucocorticoids and other steroid-sparing agents (8). Therefore, the introduction of a novel agent such as fingolimod is necessary to dogs with MUE.

Nothing is known regarding pharmacokinetics (PK) and pharmacodynamics (PD) of fingolimod in dogs. Thus, this study was performed to obtain preclinical data regarding fingolimod in dogs before the clinical applications. The objective of this study was to evaluate the PK and PD of single-dose oral fingolimod in healthy Beagle dogs.

Materials and Methods

Animals. Nine healthy Beagle dogs (four males and five females) were used. The dogs were aged 1.5-3.8 years (mean age, 2.7 years) and weighed 9.1-14.1 kg (mean weight, 11.51 kg). All dogs were healthy based on physical examination and blood analyses, such as complete blood count, chemistry, and electrolyte profile. The dogs were housed individually and acclimated before the study for more than two weeks. The room was maintained on a 12:12 h light/dark cycle at room temperature (22±0.5˚C) with constant humidity (5±10%) and an air ventilation rate of 10 cycles per h. The dogs were fed commercial dry food twice daily, and water was available ad libitum.

Study design. Nine dogs were used and classified into three groups: low-dose group (0.01 mg/kg, n=3), medium-dose group (0.05 mg/kg, n=3), and high-dose group (0.1 mg/kg, n=3). All dogs fasted for 12 h before the fingolimod administration. Oral fingolimod (Fytarex, Novartis Pharma Stein AG, Stein, Switzerland) was administered using gelatin capsules.

Each 2.25 ml sample of venous blood was obtained from the jugular vein at 0, 1, 2, 4, 6, 8, 12, 16, 20, 24, 36, 48, 72, 96, 120, 168, 240, and 336 h after fingolimod administration and divided into 2 ml and 0.25 ml K2 EDTA tubes for the measurement of data of PK and PD, respectively. The samples were inverted several times immediately to prevent clotting, and the 2 ml EDTA tubes for PK were frozen at –20˚C within 30 min of collection. The 0.25 ml EDTA tubes were used to measure leukocyte counts by subtype immediately after sampling.

This study was approved by the Institutional Animal Care and Use Committee (CBNUA-1515-21-01) of the Laboratory Animal Research Center of Chungbuk National University.

Determination of fingolimod concentration. A previous study describing validated high-performance liquid chromatography with tandem mass spectrometry was referred to determine fingolimod concentrations in the whole blood samples (9). Liquid-liquid extraction was conducted on 100 μl of whole blood samples containing internal standard by adding 50 μl of 0.1 N NaOH and 500 μl of tert-butyl methyl ether. After mixing and centrifugation, 400 μl of supernatant was dried. Dried samples were reconstituted using 200 μl of acetonitrile and analyzed using high-performance liquid chromatography (Agilent 1200 series, Agilent Technologies, Santa Clara, CA, USA) with a tandem mass spectrometry system (AB Sciex API 4000 LC-MS/MS System, SCIEX, Framingham, MA, USA) with multiple reaction monitoring modes.

Pharmacokinetics parameters. PK parameters of fingolimod were calculated by a non-compartmental analysis using WinNonlin software (Pharsight Corp., Mountain View, CA, USA). The parameters obtained were as follows: 1) time to reach maximal concentration (Tmax), 2) maximal concentration of fingolimod (Cmax), 3) dosage normalized Cmax (Cmax/dose), 4) area under the curve from the time of dosing to the last measurable concentration (AUClast), 5) dosage normalized AUClast (AUClast/dose), 6) area under the curve from the time of dosing to time infinity (AUCinf), 7) dosage normalized AUCinf (AUCinf/dose), and 8) elimination half-life of fingolimod (T1/2).

Determination and analysis of leukocyte counts by subtype. Leukocyte counts by subtype were measured using a veterinary hematology analyzer (ProCyte Dx Hematology Analyzer, IDEXX, Westbrook, ME, USA). The numbers of leukocytes by subtype were plotted against time to identify temporal trends. Effects of fingolimod were evaluated by obtaining the nadir of count and the corresponding time of nadir using time-leukocyte subtype curves. Normal reference intervals for leukocytes by subtype (used by our institution) were 1.05-5.1×109 cells/l, lymphocytes; 0.06-1.23×109 cells/l, eosinophils; 2.95-11.64×109 cells/l, neutrophils; 0.16-1.12×109 cells/l, monocytes; and 0-0.1×109 cells/l, basophils.

Adverse effects. Adverse effects were monitored during the experimental period. To identify bradycardia, one of the representative adverse effects of fingolimod, heart rates in the low- and the high-dose group were measured simultaneously as PK and PD for a day.

Statistical analyses. Statistical analyses were performed using commercial software (Prism 9.0, Graphpad Software Inc, San Diego, CA, USA). A 2-sided p-value <0.05 was considered statistically significant. The assessment of normal distribution was performed using the Shapiro–Wilk test, and a normal distribution was not identified. The Friedman test was employed to identify a significant reduction of leukocyte counts by subtype and heart rate changes compared to baseline (0 h) after fingolimod administration.

Results

Pharmacokinetics. Mean whole blood concentration-time curves are shown in Figure 1, and the corresponding PK parameters are shown in Table I. Following the administration of oral fingolimod dosing at 0.01 mg/kg (low-dose), 0.05 mg/kg (medium-dose), and 0.1 mg/kg (high-dose), Cmax was estimated to be 0.6 ng/ml, 3.7 ng/ml, and 4.8 ng/ml, which was observed at 12.0 h, 14.7 h, and 21.3 h post-dose, respectively. AUClast was 41.4 ng•h/ml, 238.6 ng•h/ml and 311.1 ng•h/ml at 0.01 mg/kg, 0.05 mg/kg, and 0.1 mg/kg, respectively, and AUCinf was 52.3 ng•h/ml, 318.0 ng•h/ml and 361.1 ng•h/ml at 0.01 mg/kg, 0.05 mg/kg, and 0.1 mg/kg, respectively. After reaching maximal concentration, whole blood concentration decreased slowly with T1/2 of 69.4 h, 74.9 h, and 49.5 h at 0.01 mg/kg, 0.05 mg/kg, and 0.1 mg/kg, respectively.

Figure 1. Mean whole blood concentration-time curves following a single dose of oral fingolimod at doses of 0.01 mg/kg, 0.05 mg/kg, and 0.1 mg/kg in normal Beagle dogs. Data are mean±SD.

Figure 1

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Table I. PK parameters for a single oral dose of fingolimod.

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All data are expressed as mean±SD. AUClast: The area under the curve from dosing to the last measurable concentration; AUClast/dose: dosage normalized AUClast; AUCinf: the area under the curve from dosing to time infinity; AUCinf/dose: dosage normalized AUCinf; Cmax: maximal concentration; Cmax/dose: dosage normalized Cmax; T1/2: elimination half-life; Tmax: time to reach maximal concentration; PK: pharmacokinetic.

Pharmacodynamics. Figure 2 shows the change in the numbers of leukocytes by subtype over two weeks after fingolimod administration. The number of lymphocytes significantly decreased compared to baseline in all dose groups (low-dose, p=0.0002; medium-dose, p<0.0001; high-dose, p=0.0012). The nadirs of lymphocyte count in the low-, medium-, and high-dose groups were 1.52×109 cells/l (nadir time, 12 h), 0.6×109 cells/l (nadir time, 16 h and 36 h), and 0.52×109 cells/l (nadir time, 36 h), respectively. The number of eosinophils significantly decreased compared to baseline in the low- and medium-dose groups (low-dose, p=0.0006; medium-dose, p=0.0006). The nadirs of eosinophil count in the low- and medium-dose groups were 0.1×109 cells/l (nadir time, 12 h) and 0.05×109 cells/l (nadir time, 36 h), respectively. The number of neutrophils significantly decreased compared to baseline in the medium- and high-dose groups (medium-dose, p=0.0345; high-dose, p=0.0016). The nadirs of neutrophil count in the medium- and the high-dose groups were 3.3×109 cells/l (nadir time, 48 h) and 4.7×109 cells/l (nadir time, 96 h), respectively. The number of monocytes significantly increased compared to baseline in the medium-dose group (p=0.0297). The zenith of monocyte count in the medium-dose group was 0.57×109 cells/l (zenith time, 96 h). The number of basophils did not show a significant change after the administration of fingolimod.

Figure 2. Mean leukocytes trajectories after administration of single-dose fingolimod in low- (0.01 mg/kg), medium- (0.05 mg/kg), and high- (0.1 mg/kg) dose groups. (A) The number of lymphocytes significantly decreased compared to baseline in all dose groups (low-dose, p=0.0002; medium-dose, p<0.0001; high-dose, p=0.0012). (B) The number of eosinophils significantly decreased compared to baseline in the low- and medium-dose groups (low-dose, p=0.0006; medium-dose, p=0.0006). (C) The number of neutrophils significantly decreased compared to baseline in the medium- and high-dose groups (medium-dose, p=0.0345; high-dose, p=0.0016). (D) The number of monocytes significantly increased compared to baseline in the medium-dose groups (p=0.0297). (E) The number of basophils did not show significant changes after administration of fingolimod. Friedman test. *p<0.05; **p<0.01; ***p<0.001; ****p<0.0001.

Figure 2

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Adverse effects. A single dose of fingolimod was well tolerated in all dogs. There were no adverse events or significant clinical changes. To identify transient bradycardia that is one of the most representative adverse effects, the heart rates of the low- and high-dose groups were monitored. The heart rates over time were all within the normal range, and there were no significant changes (low-dose, p=0.2257; high-dose, p=0.1237) compared with baseline after administration of fingolimod for one day (Figure 3).

Figure 3. Change of heart rate after single-dose oral administration of fingolimod for one day. In both the low- (0.01 mg/kg) and high- (0.1 mg/kg) dose groups, all heart rates were within normal range, and there was no significant change compared to baseline heart rate (0 h). p>0.05, Friedman test.

Figure 3

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Discussion

This preliminary study provides the first PK and PD data of oral fingolimod in dogs. The concentration (i.e., Cmax and AUC) of fingolimod in the blood increased dose-dependently following administration of 0.01 to 0.1 mg/kg fingolimod. Fingolimod reduced lymphocyte count dose-dependently up to the dose of 0.05 mg/kg without adverse effects. These findings provide the basis for future clinical applications of fingolimod in dogs with MUE.

There are five subtypes of S1PRs (10). S1PR1 is the main receptor expressed on lymphocytes, and it has a dominant role in regulating lymphocyte trafficking (4). Fingolimod is an S1PR modulator and prevents CNS infiltration of lymphocytes by sequestering lymphocytes from lymphoid organs by binding to S1PR1 on lymphocytes (4,5). In a human single-dose study with twice the clinical dose, a 38% decrease in lymphocyte count was observed at 22 h after fingolimod administration (9). This nadir lymphocyte count showed a gradual recovery over the subsequent week (9).

In the present PK study of fingolimod, its concentration (i.e., Cmax and AUC) increased dose-dependently following oral administration of 0.01 to 0.1 mg/kg fingolimod, but it was not proportional. In the PD study of fingolimod, the alteration of lymphocytes count was remarkable by increase of dose, suggesting the presence of fingolimod in the blood directly decrease the lymphocytes. The peripheral lymphocyte count declined in the low-, medium-, and high-dose groups by 50.3% (nadir time, 12 h), 80.4% (nadir time, 16 h and 36 h), and 81.2% (nadir time, 36 h), respectively. It was found that the effect of fingolimod increased as the dose was elevated from the low to the medium dose. Still, it was also found that there was no difference in reducing lymphocyte count above the medium dose. The recovery of lymphocytes in the blood was slower in the higher dose group, indicating the recovery is delayed in high dose; two days (low-dose), 10 days (medium-dose), and >14 days (high-dose). Based on the PD results, the recommended dose of fingolimod is 0.01–0.05 mg/kg.

A significant reduction in eosinophils (low- and medium-dose groups) and neutrophils (medium- and high-dose groups), as well as lymphocytes, was found in this study. Not humans but cats also showed reduced neutrophils following fingolimod administration (11). S1PRs are also expressed on various other immune cells besides lymphocytes (12). S1PR1 is ubiquitously expressed in all types of immune cells. S1PR2, S1PR3, and S1PR4 are expressed on macrophages, monocytes, eosinophils, and mast cells. S1PR3 and S1PR4 are expressed neutrophils and dendritic cells, and S1PR5 is expressed on the patrolling monocytes and natural killer cells (12). Fingolimod activates various S1PRs except for S1PR2 (13,14). Therefore, fingolimod could be used for inflammatory or immune-mediated diseases involving eosinophils or neutrophils.

The most common adverse effects of fingolimod in humans are infection, hypertension, headache, increased liver enzymes, and gastrointestinal signs (nausea, diarrhea, vomiting) (2). The representative adverse effects related to cardiac events are bradycardia and atrioventricular block (2,15-18). Although cardiac adverse effects are not common compared to other adverse effects, they can be clinically problematic. Therefore, the pharmaceutical company that produces fingolimod states that all patients should be assessed for bradycardia 6 h after administration (15). S1PRs are strongly expressed on cardiomyocytes and endothelial cells in the atrium and ventricle (19,20). Its agonistic properties could induce the cardiac effects of fingolimod on the heart rate because S1PRs are expressed in cardiac tissues (21,22). Therefore, acute transient and dose-dependent heart rate reduction could be induced after administering the first dose, but it is generally asymptomatic and self-limiting (2). In this study, a significant change in heart rate was not observed following the administration of a single dose of fingolimod. Although the heart rate of the high-dose group showed relative reduction compared to baseline heart rate, no significant change was observed.

This study has some limitations. First, immunohistochemical staining for S1PRs was not performed in dogs. However, it was found that fingolimod could be effective in reducing peripheral lymphocytes. Second, multi-dose PK and PD that are more suitable for the clinical setting than single-dose experiments were not performed. Third, blood analysis was not performed to detect the adverse effects. Fourth, the sample size was too small to show statistical significance. Therefore, additional studies with larger sample sizes should be performed.

Conclusion

This preliminary study was the first to investigate the PK and PD of fingolimod in dogs. The concentration of fingolimod in the blood increased non-proportionally when the administration dose increased from 0.01 to 0.1 mg/kg. The fingolimod was well tolerated and effective, inducing a rapid reduction of peripheral lymphocytes, eosinophils, and neutrophils without adverse effects at a dose from 0.01 mg/kg to 0.1 mg/kg. For lymphocytes, it was found that the effect of fingolimod increased as the dose was increased from 0.01 to 0.05 mg/kg, and it was also found that there was no difference in reducing lymphocyte count with doses above 0.05 mg/kg. The recovery of lymphocytes in blood was slower at higher doses. Therefore, this study will be the basis for the clinical application of fingolimod as a novel agent for MUE or other immune-mediated diseases although long-term PK/PD and adverse effects of multi-doses were not assessed and need to be investigated.

Conflicts of Interest

The Authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Authors’ Contributions

TY and BTK contributed to the conception and design of the research. TY, JWJ and KRL performed the experiments and interpreted the results. TY, YK, YC, and DL were involved in data collection. HK, SK, MPY and BTK contributed to the editing, revising, and final approval of the article. All Authors critically revised the article and read and approved the final version.

Acknowledgements

This work was supported by a National Research Foundation of Korea (NRF) grant funded by the Korean government (MSIT) (No. 2021R1A2C1012058) and the Basic Research Lab Program (2022R1A4A1025557) through the NRF of Korea funded by the Ministry of Science and ICT.

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